It may not be marked on your calendar, but today, March 24 is World TB Day , created to remind people of the massive global health problem caused by tuberculosis. On this day in 1882, the brilliant microbiologist Dr. Robert Koch announced his stunning discovery that TB is caused by infection with a bacterium, Mycobacterium tuberculosis. At the time, TB killed one in seven people in Europe and the Americas. Now, 132 years later, TB still kills more people than any other infection save AIDS – and many AIDS patients worldwide actually die of TB. Why does TB continue to rage despite decades of scientific progress, and why am I nonetheless hopeful that great improvements in stopping TB are possible?

The circular M. tuberculosis genome is shown with all genes drawn in the blue and orange rings. The complex and dynamic expression of these genes is controlled by a class of regulators called transcription factors. Transcription factors exert their influence by interacting with small molecules, each other, and ultimately the DNA to change gene expression in response to a given condition. The M. tuberculosis genome encodes over 200 transcription factors, and in collaboration with others we have characterized the regulatory capacity of nearly all of these control genes. In this figure the colored lines depict the location of the transcription factor and its bound targets. This figure is drawn from a subset of all binding data, including only the most significant binding events for the most abundant family of transcription factor in M. tuberculosis. Regions of binding hotspots are depicted by green spikes radiating out from the gene rings. / Figure created by Kyle J. MInch

First, a few dismal facts. TB spreads when an infected person coughs or sneezes, a method so efficient that 1.8 billion people or roughly 30 percent of all living persons harbor latent TB, defined as an infection in the absence of symptoms. Globally, someone develops active TB every four seconds, and someone dies from TB every 20 to 30 seconds – and our tools to combat this scourge are almost universally outdated and overmatched. The chief TB diagnostic worldwide, purified protein derivative (PPD), is over 100 years old, fails to distinguish between latent infection and active disease, and results are harder to interpret in those who have been vaccinated. The TB vaccine is nearly 100 years old and widely used, but its lack of effectiveness is evident from the sheer size of the current pandemic. TB is treated with drugs – a complex mix of four agents over six months that has not been updated in almost 50 years. Not surprisingly, drug resistance has been steadily rising. Currently about 5 percent of all cases are resistant to the key TB drugs and as the number of drugs a strain resists increases, the treatment options grow increasingly desperate. As bad as all that might be, the TB field also suffers from an enormous funding gap. The World Health Organization (WHO) estimates that an additional $1.6 billion is needed per year for treatment and an additional $1.4 billion per year for research. Altogether this disease is becoming increasingly difficult to stop with our current tools and resources.

TB is painstakingly slow. People can be latently infected for years or decades before developing active illness, which then takes months or even years to resolve. The TB bacterium is also slow in the lab, where a single bacterium takes three weeks to form a colony on agar plates. In addition to patience, TB researchers need highly specialized and expensive containment facilities to keep from infecting themselves and others. Compare TB with a basic science workhorse, Escherichia coli. This model organism and occasional pathogen forms colonies in a day and can be manipulated on the equivalent of a high school lab bench. Decades ago, when TB was still a leading killer in the U.S., TB research was a cutting-edge field attracting top talent and generating Nobel Prize discoveries. Then the threat receded in the developed world, and attention moved to faster and less dangerous fields of study.

Despite this, I remain optimistic and determined. We are beginning to make real inroads against TB, using the best tools at our disposal: science and organization.

The current state of TB science is fascinating. The molecular biology revolution barely touched the TB field until the 1990s. Then researchers with new approaches turned to the problem, and the scientific contradictions that confront the field began to come into sharper focus. TB is an infection that, because it plays out over years, sometimes closely resembles chronic diseases. Despite its slow growth, TB spreads through populations very effectively. Yet despite its remarkable success as a pathogen, TB is not especially pathogenic. About 90 percent of those infected with TB will effectively contain the disease, as long as they avoid immune-suppressing conditions such as HIV. A person with the active disease will likely have many discrete TB lesions in their lungs, comprised of a delicate interplay of bacteria with different immune cells and microenvironments. In most of those lesions, the bacteria and the disease will be well contained while in the same lung there may be one or two lesions that for unknown reasons explode with bacterial replication, inflammation and tissue damage that ultimately threaten the person’s life. Except in resistant cases, drugs rapidly kill nearly all the TB bacteria, but therapy must be continued for six months to prevent relapses.

This biological pas de deux demands a nuanced response from the researcher. In my lab we have turned largely to the tools of systems biology. Nearly all biological research is reductionist, focusing on individual genes, products and processes. Obviously this approach has been extremely successful, but breakthroughs in some fields such as TB have proven elusive. The convergence of technologies, computation and systems thinking offers a way to change this equation. Systems biology allows us to interrogate the behaviors of all genes, all RNAs, all proteins, etc. together, focusing on the overall behavior of interacting networks within the system and then creating predictive models of the disease. For example, my lab recently collaborated to produce the first experimentally-leveraged, large-scale gene regulatory network for the TB bacterium. This work exposes the genetic wiring within a TB cell, and offers an unprecedented chance to understand how the bacteria adapt to complex and changing environments within infected humans. More broadly, by combining high throughput experimental analysis, mathematical modeling and computation, along with expertise in TB biology and immunology, we and others hope to identify the molecular networks that are key to developing the next generation of drugs and vaccines.

Because it primarily affects poor people in poor countries throughout the world, combatting TB has always presented significant organizational challenges as well. In particular, wealthy governments don’t always maintain focus on expensive troubles happening elsewhere, and drug and vaccine manufacturers tend to avoid taking on big problems where the potential financial payoff is small. Still, in the past 15 or so years, interested people with a wide range of expertise and agendas have sought new ways to work together in the TB fight. New organizations that involve academics, activists, government agencies, philanthropists, private industry and public-private partnerships are transforming the global approach to TB research and treatment. For example, non-profits such as the Foundation for Innovative New Diagnostics, the TB Alliance and Aeras have recently established themselves as key global participants in the pursuit of new TB diagnostics, drugs and vaccines, respectively. My own TB research has collaborated with three different pharmaceutical companies (mostly donating their time and resources), along with several non-profit institutes and numerous academics around the world, with funding from the National Institutes of Health (NIH) and at least three different philanthropic groups. This dissociated, network approach is not unique to TB – people focused on malaria and other major issues of global health are organizing in similar ways to generally positive effect. It does not take a systems biologist to see that this network model is more robust than individuals trying to solve the problem on their own.

Through new science and organizational means, we are trying to tackle problems where the old paradigm of government-funded research and industry-driven product development has failed to meet the global need. And these efforts are starting to bear fruit. 2010 saw the introduction of GeneXpert, the first major advance in TB diagnostics since the days of Robert Koch. Last year, a new TB drug, Bedaquiline was approved for the first time in nearly 50 years. Perhaps more impressive, multiple point-of-care TB tests and at least a dozen TB vaccine candidates are in development, and about ten TB drugs and combinations are now in clinical trials. Much, much more is needed to stem the tide of the TB pandemic, but after decades of neglect, the picture finally includes room for real optimism.

So happy World TB Day. Stay informed. Be optimistic. And try not to cough on anyone.

The views expressed are those of the author(s) and are not necessarily those of Scientific American.

ABOUT THE AUTHOR(S)

David Sherman

As a professor at Seattle Biomedical Research Institute (Seattle BioMed), David Sherman studies the virulence and latency of Myocbacterium tuberculosis, and is also engaged in developing novel drugs directed against this tenacious pathogen. He began work on M. tuberculosis while working at a biotech firm, where he played a lead role in the discovery and early development of the anti-TB agent PA-824 that is now in clinical trials. He earned his Ph.D. in Biochemistry from Vanderbilt University, and performed post-graduate work at the Rockefeller University and at Washington University in St. Louis.
Sherman's current projects include a detailed analysis of the M. tuberculosis gene regulatory network in vitro and in vivo, and the pursuit of latency-relevant drug targets. His laboratory routinely employs a variety of research tools, including molecular genetics, systems biology, biochemistry, cultivation in vitro and in vivo, and whole genome microarray analysis.

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